The compounds and methods proposed by this invention are related to essentially a mixture of naturally accruing and other substances to produce a novel compound that exhibits strong anti-inflammatory, muscle relaxant, and analgesic qualities. A plurality of medicinal concoctions can be manufactured from said compound that have various pharmacological effects and different routes and methods of administration. The active ingredients of said compounds can be derived from Mitragyna speciosa (Kratom) and Cannabis sativa plants or can be chemically synthesized.
Mitragyna speciosa is an evergreen tree of the coffee (Rubiaceae) family native to Indonesia, Malaysia, Myanmar, Papua New Guinea, Indonesia, and Thailand. It is best known for generating leaves that contain more than 40 distinct psychoactive compounds. Mitragyna speciosa plant is a 4 to 16-meter-high tropical tree indigenous to South East Asia but now cultivated elsewhere. In Thailand, the tree and leaf preparations are called Kratom. Traditionally, fresh or dried Kratom leaves are chewed or made into a tea; they are seldom smoked. At a low dose, Kratom has stimulant effects and it is used to combat fatigue during long working hours. At high dosages, however, it has sedative-narcotic effect. It is also used in traditional medicine and as an opium substitute.
As already mentioned, the phytochemicals isolated from various parts of the tree include over 40 structurally related alkaloids as well as several flavonoids, terpenoid saponins, polyphenols, and various glycosides. The main psychoactive components in the leaves are mitragynine and 7-hydroxymitragynine, both found only in Mitragyna speciosa. Kartom contains other central nervous system stimulants and depressants that can act upon a variety of neurotransmitter systems within the human brain. As already mentioned, it has traditionally been consumed as a leaves decoction for its stimulant effects to counter fatigue, treat fever, diarrhea, as well as anesthetic, antinociceptive, analgesic and stimulating effects that help to combat fatigue and suppress appetite.
Cannabis sativa (marijuana) is an annual herbaceous flowering plant indigenous to eastern Asia but now of cosmopolitan distribution due to cultivation. It is placed in the Cannabis genus classification, which belongs to a small but diverse family, the Cannabaceae. Cannabinoid (CB) components of marijuana are known to exert behavioral and psychotropic effects but also to possess therapeutic properties including analgesia, ocular hypotension, and antiemesis. CBs-based medications are now being used for treatment of a wide range of medical conditions, including neuropathic pain, pain related to cancer and trauma, spasticity associated with Multiple Sclerosis (MS), fibromyalgia, and others.
This invention generally relates to pharmaceutical compounds and methods for reducing muscle fatigue and spasticity, reducing inflammation, and treating pain associated with cancer, trauma, medical procedure, and neurological diseases and disorders in subjects in need thereof, as well as a method of administering therapeutically-effective amount of said pharmaceutical compound containing certain natural and/or synthetic Mitragyna speciosa and Cannabis sativa alkaloids and/or their derivatives/analogs and other substances.
Other medical conditions are also contemplated by this invention that include, but are not limited to: Huntington's Disease (HD); Wilson's Disease; Parkinson's Disease (PD); metabolic and endocrine diseases and disorders; athetosis-related to damage or degeneration of basal ganglia; minor tranquilizers, alcohol, cocaine, (meta)amphetamine, and opioid withdrawal syndromes; symptoms or side effects associated with anti-retroviral therapy, chemotherapy and radiation therapy; AIDS; rheumatoid arthritis; osteoarthritis; fibromyalgia; pain and spasticity associated with MS, Neuromuscular Junction Disorder and other neurodegenerative disease, autoimmune diseases and disorders, motor neuron diseases and disorders, neurodegenerative diseases and disorders; pain associated with cancer; trauma; athletic performance; migraine; surgical intervention or medical treatment; dental and gum pain; stroke; heart attack; abdominal pain; bone pain, muscle pain; neurological pain; stomach ulcers-related pain; gallbladder disease-related pain; Central Pain Syndrome; chronic pain disorder (nociceptive pain, neuropathic pain, chronic back or leg pain, painful neuropathies, Complex Regional Pain Syndrome), and acute pain.
The principal mechanism of Kratom's psychoactive action involves mu-opioid receptor partial agonism, and to a lesser extent, kappa-opioid receptor antagonism—relatively analogous to the drug buprenorphine. Other, less prominent, mechanisms of Kratom's action include: delta-opioid receptor antagonism, alpha-2 receptor agonism, 5-HT2A receptor antagonism, and adenosine A2A receptor antagonism. Due to the aforesaid pharmacodynamics, when ingested, most individuals report opioidergic and/or stimulatory effects.
CBs are a group of chemicals known to activate CB receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals, these are termed endocannabinoids. There are also synthetic CBs that are chemicals with similar structures to plant CBs or endocannabinoids. Plant cannabinoids can also be isolated such that they are “essentially pure” compounds. These isolated CBs are largely free of other naturally occurring compounds, such as other minor CBs and molecules.
The primary CB receptor subtypes are CB receptors type 1 (CB1) and type 2 (CB2). CB1 receptors are highly expressed in the Central Nervous System (CNS), especially the basal ganglia, and also identified in almost all peripheral tissues and cell types. CB2 receptors are expressed primarily in the immune system, where they modulate inflammation, but are also expressed in the CNS, particularly in neurons within the dorsal vagal motor nucleus, the nucleus ambiguous, the spinal trigeminal nucleus, and microglia. CB2 receptors were also found in the basal ganglia and studies suggest that impairment of these receptors may be associated with dyskinesia. While most actions of CBs are related to CB1 and CB2 receptors, other receptor types have been described, including the Transient Receptor Potential Vanilloid type 1 (TRPV1) cation channel, the GTP-binding Protein-coupled Receptor GPR55, the abnormal-CBD receptor, and the Peroxisome-Proliferator-Activated Receptor (PPAR).
Endogenously produced CBs (eCBs) are lipophilic compounds that demonstrate varying degrees of affinity for G-protein coupled CB receptors and include anandamide and 2-arachidonoglycerol. eCBs primarily function through retrograde signaling, wherein post-synaptic activity leads to eCB production and release with backward transmission across the synapse to depress presynaptic neurotransmitter release. The Endo-Cannabinoid System (ECS) may also support synapse formation and neurogenesis. Within the basal ganglia, eCBs and CB1 receptors tend to increase GABAergic and inhibit glutamatergic transmission. eCBs also tend to inhibit dopamine release through GABAergic mechanisms. eCBs are not stored and are quickly degraded after exerting a transient and localized effect. Removal of eCBs from the extracellular space occurs through cellular uptake and metabolism with anandamide degraded primarily by Fatty Acid Amide Hydrolysis (FAAH) and 2-AG degraded by monoacylglycerol lipase.
The disclosed invention finds that, in one embodiment, a number of alkaloids contained in Mitragyna speciosa and Cannabis sativa plants, when combined, could be used as a substitute for morphine, having a potent analgesic action, and can provide a sedative and muscle relaxant effects akin to the effects of benzodiazepines. Mitragynine and 7-hydroxymitragynine, found in Mitragyna speciosa, as well as tetrahydrocannabinol (THC) and cannabidiol (CBD), found in Cannabis sativa, are the two groups of alkaloids mainly responsible for the analgesic and muscle relaxant effects. Mitragynine and 7-hydroxymitragynine are partial agonists of the μ-subtype opioid receptor (MOR) (Kruegel, et al., 2016). In mice, 7-hydroxymitragynine was thirteen times more potent analgesic than morphine even upon oral administration (Matsumoto, et al., 2004). The effect of Kratom alkaloids as opioid receptor agonist is confirmed by the fact that it is readily antagonized by the opioid receptor antagonist naloxone (Yamamoto, et al., 1999). In addition, 5-HT2a and postsynaptic α2-adrenergic receptors, as well as neuronal Ca2+channels are also involved in the unique pharmacological and behavioral activity of mitragynine.
In addition, mitragynine exhibits antinociceptive and cough-suppressant effects that are comparable to those of codeine in animal studies (Macko, Weisbach, & Douglas, 1972). It has been reported that a methanol extract of Kratom leaf and a major alkaloid, mitragynine, produced skeletal muscle relaxation. Thus, mitragynine also has a direct effect on skeletal muscle by decreasing the muscle twitch. More so, Chittrakarn et al. (2010), report that Kratom extract had a greater effect at the neuromuscular junction than on the skeletal muscle or somatic nerve.
With CBs, likewise, a number of clinical trials in humans demonstrated that CBs might be useful in the treatment of movement disorders and pain. It has been suggested that an endogenous CBs participate in the control of movements and, therefore, the central ECS might play a role in the pathophysiology of these diseases. There is also evidence that CBs are of therapeutic value in the treatment of tics in Tourette Syndrome (TS), the reduction of Levodopa-Induced Dyskinesia (LID) in PD and some forms of tremor and dystonia. There is also evidence that CBs are useful in the treatment of chorea in HD and hypokinetic parkinsonian syndromes. Currently, treatments of these and similar diseases are focused on relieving symptoms and preventing complications because there is no curative therapy. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of PD and HD. Clinical observations and clinical trials of CB-based therapies suggest a possible benefit of CBs for tics.
Kratom extract contains multiple alkaloids, where some of them have therapeutic potential. The following activity effects and concentrations are compiled from several studies of alkaloids and their concentrations in Mitragyna speciosa. Results of one of the studies is presented in FIG. 2. The following list, though, is not inclusive and the alkaloids shall be further studied to determine their activity: ajmalicine (raubasine)—cerebrocirculant, antiaggregant, anti-adrenergic (at alpha-1), sedative, anticonvulsant, smooth muscle relaxer (found in Rauwolfia serpentine); ciliaphylline—antitussive, analgesic <1% of total alkaloid content found in Kratom leaf; corynantheidine—μ-opioid antagonist (also found in Yohimbe)<1% of total alkaloid content found in Kratom leaf; corynoxeine—calcium channel blocker <1% of total alkaloid content found in Kratom leaf; corynoxine—dopamine mediating anti-locomotives <1% of total alkaloid content found in Kratom leaf; epicatechin—antioxidant, antiaggregant, antibacterial, antidiabetic, antihepatitic, anti-inflammatory, anti-leukemic, antimutagenic, antiperoxidant, antiviral, potential cancer preventative, alpha-amylase inhibitor (also found in dark chocolate); 9-hydroxycorynantheidine—partial opioid agonist; 7-hydroxymitragynine—analgesic, antitussive, antidiarrheal; primary psychoactive in Kratom, approximately 2% of total alkaloid content found in Kratom leaf; isomitraphylline—immune-stimulant, anti-leukemic <1% of total alkaloid content found in Kratom leaf; isomitrafoline <1% of total alkaloid content found in Kratom leaf; isopteropodine—immuno-stimulant; isorhynchophylline—immuno-stimulant <1% of total alkaloid content found in Kratom leaf; isospeciofoline: <1% of total alkaloid content found in Kratom leaf; mitraciliatine <1% of total alkaloid content found in Kratom leaf; mitragynine—indole alkaloid, analgesic, antitussive, antidiarrheal, adrenergic, antimalarial, possible psychedelic (5-HT2A) antagonist, approximately 66% of total alkaloid content found in Kratom leaf; mitragynine oxindole B<1% of total alkaloid content found in Kratom leaf; mitrafoline <1% of total alkaloid content found in Kratom leaf; mitraphylline—oxindole alkaloid, vasodilator, antihypertensive, muscle relaxer, diuretic, antiamnesic, anti-leukemic, possible immunostimulant <1% of total alkaloid contents in Kratom leaf; paynantheine—indole alkaloid, smooth muscle relaxer, 8.6% to 9% of total alkaloid contents in Kratom leaf; rhynchophylline—vasodilator, antihypertensive, calcium channel blocker, antiaggregant, anti-inflammatory, antipyretic, anti-arrhythmic, antithelmintic <1% of total alkaloid content found in Kratom leaf; speciociliatine—weak opioid agonist, 0.8% to 1% of total alkaloid content of Kratom leaf, unique to Kratom; speciogynine—smooth muscle relaxer, 6.6% to 7% of total alkaloid contents of Kratom leaf; speciophylline—indole alkaloid, anti-leukemic <1% of total alkaloid contents of Kratom leaf; tetrahydroalstonine—hypoglycemic, anti-adrenergic (at alpha-2).
As in all botanicals, Mitragyna speciosa and Cannabis sativa alkaloid content varies quantitatively from geographical location, and from month to month, at different leaf harvest times. This led some teams to conclude that there may be different geographical variants within the same species. The Chelsea College Pharmacognosy Research Laboratories collected thirty samples of Kratom from Thailand, Malaysia, and Papua New Guinea between 1961 and 1970. All contained mitragynine, but also proved to have considerable variation in the alkaloid makeup. For red and green/white leaved plants of Thailand, the most common alkaloidal profile was mitragynine, speciogynine, speciociliatine, paynantheine, traces of ajmalicine, traces of (C9) methoxy-oxindoles, and traces of other indoles.
Yet other Thai plants contained distinct alkaloidal profiles, some with many more alkaloids. In the Malay specimens, one contained mitragynine, speciofoline, and other indoles and oxindoles, while others contained mitragynine, ajmalicine, speciogynine, speciociliatine, paynantheine, traces of indoles, and (C9) methoxy-oxindoles. Specimens from Papua New Guinea contained mitragynine, speciogynine, speciociliatine, paynantheine, specionoxeine, and isospecionoxeine. Other researchers reported that Thai and Malay Kratom had the alkaloids mitragynine, speciogynine, speciociliatine, paynantheine and 7-hydroxymitragynine in common.
In both Thai and Malay samples, mitragynine was the most abundant alkaloid, yet it made up 66% of the total alkaloid in the Thai Kratom sample, while it made up only 12% of the alkaloids from the Malaysian sample. The Malay Kratom sample had mitragynaline and pinoresinol as major components, as well as mitralactonal, mitrasulgynine and 3,4,5,6-tetradehydromitragynine. In the Malay Kratom, 4 new types of indole alkaloids (corynantheidaline, corynantheidalinic acid, mitragynaline and mitragynalinic acid) were discovered in very young leaves.
Likewise, Cannabis sativa alkaloid content and yield also depends on the plant type (drug, fiber), pollination, sex, age, part of the plant, cultivation (indoor, outdoor etc.), harvest time and conditions, drying, as well as storage. From 1980 to 1997, a total of 35,213 samples of confiscated Cannabis products (Cannabis, hashish, hashish oil) representing more than 7717 tons seized in the United States were analyzed by gas chromatography (GC). The mean THC concentration increased from less than 1.5% in 1980 to 4.2% in 1997. The maximum levels found were 29.9 and 33.1% in marijuana and sinsemilla Cannabis, respectively, where the highest THC concentrations measured were 52.9 and 47.0%, respectively. Concentration of THC in marijuana has lately increased significantly due to the progress in breeding, the tendency to cultivate under indoor conditions, and the worldwide access to and exchange of seeds originating from high-THC cultivars via the Internet. However, this is not the case when it comes to CBD, it is rare to find such high numbers. Any CBD content level that is 4% or higher is considered a high CBD strain. Strains with up 18% CBD have emerged in the last several years, but commercially available high CBD strains contain on average between 8-12% CBD.
The Cannabis sativa plant and its products consist of many chemicals. Some of the 483+ compounds identified are unique to Cannabis, for example, more than 60 cannabinoids, whereas the terpenes, with about 140 members forming the most abundant class. So far, 66 cannabinoids have been identified, and they are divided into 10 subclasses: 1) Cannabigerol class: cannabigerolic acid (CBGA)—antibiotic; cannabigerolic acid monomethylether (CBGAM); cannabigerol (CBG)—antibiotic, antifungal, anti-inflammatory, relaxant (possibly inhibits the uptake of GABA); cannabigerol monomethylether (CBGM); cannabigerovarinic acid (CBGVA); cannabigerovarin (CBGV); 2) Cannabichromene class: cannabichromenic acid (CBCA); cannabichromene (CBC)—anti-inflammatory, antibiotic, antifungal, analgesic; cannabichromevarinic acid (CBCVA); cannabichromevarin (CBCV); 3) Cannabidiol class: cannabidiolic acid (CBDA)—antibiotic; cannabidiol (CBD)—anxiolytic, antipsychotic, analgesic, anti-inflammatory, antioxidant, antispasmodic; cannabidiol monomethylether (CBDM); cannabidiol-C4 (CBD-C4); cannabidivarinic acid (CBDVA); cannabidivarin (CBDV); cannabidiorcol (CBD-C1); 4) Delta-9-tetrahydrocannabinol class: delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (THC)—euphoric analgesic, anti-inflammatory, antioxidant, antiemetic; delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabinol-C4 (THC-C4); delta-9-tetrahydrocannabivarinic acid (THCVA); delta-9-tetrahydrocannabivarin (THCV)—analgesic, euphoriant; delta-9-tetrahydrocannabiorcolic acid (THCA-C1); delta-9-tetrahydrocannabiorcol (THC-C1); delta-7-cis-iso-tetrahydrocannabivarin; 5) Delta-8-tetrahydrocannabinol class: delta-8-tetrahydrocannabinolic acid (Δ8-THCA); delta-8-tetrahydrocannabinol (Δ8-THC)—similar to THC (less potent); 6) Cannabicyclol class: cannabicyclic acid (CBLA); cannabicyclol (CBL); cannabicyclovarin (CBLV); 7) Cannabielsoin class: cannabielsoic acid A (CBEA-A); cannabielsoic acid B (CBEA-B); cannabielsoin (CBE); cannabinol (CBN)—sedative, antibiotic, anticonvulsant, anti-inflammatory; cannabinol methylether (CBNM); cannabinol-C4 (CBN-C4); cannabivarin (CBV); cannabinol-C2 (CBN-C2); cannabiorcol (CBN-C1); cannabinadiol (CBND); cannabinodivarin (CBVD); 8) Cannabitriol class: cannabitriol (CBT); 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol; 8,9-dihydroxy-delta-6a-tetrahydrocannabinol; cannabitriolvarin (CBTV); ethoxy-cannabitriolvarin (CBTVE); 8) Miscellaneous cannabinoids class: dehydrocannabifuran (DCBF); cannabifuran (CBF); cannabichromanon (CBCN); cannabicitran (CBT); 10-oxy-delta-6a-tetrahydrocannabinol (OTHC); delta-9-cis-tetrahydrocannabinol (cis-THC); 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol (OH-iso-HHCV); cannabiripsol (CBR); trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC).
The typical scent of Cannabis results from about 140 different terpenoids—isoprene units (C5H8) form monoterpenoids (C10 skeleton), sesquiterpenoids (C15), diterpenoids (C20), and triterpenoids (C30). Terpenoids may be acyclic, monocyclic, or polycyclic hydrocarbons with substitution patterns including alcohols, ethers, aldehydes, ketones, and esters.
The essential oil (volatile oil) from Cannabis sativa can easily be obtained by steam distillation, vaporization, or other extraction methods. As already mentioned, the yield depends on the plant type, pollination, sex, age, part of the plant, cultivation (indoor, outdoor etc.), harvest time, drying, storage, etc. For example, fresh buds from an Afghani variety yielded 0.29% essential oil; where drying and storage reduced the content from 0.29% after 1 week and 3 months to 0.20% and 0.13%, respectively. Monoterpenes showed a significantly greater loss than sesquiterpenes, but none of the major components completely disappeared in the drying process. About 1.3 L of essential oil per ton, resulted from freshly harvested outdoor-grown Cannabis sativa, corresponding to about 10 L/ha.
The yield of nonpollinated (sinsemilla) plant at 18 L/ha was more than twofold compared with pollinated (8 L/ha). Sixty-eight components were detected by GC and GC/mass spectrometry in fresh bud oil distilled from high-potency, indoor-grown Cannabis sativa. Further, 57 constituents have been identified, where 92% were monoterpenes, 7% sesquiterpenes, and approximately 1% were other compounds. The dominating monoterpenes were myrcene (67%) and limonene (16%). In the essential oil from outdoor-grown Cannabis sativa, the monoterpene concentration varied between 47.9 and 92.1% of the total terpenoid content, and the sesquiterpenes ranged from 5.2 to 48.6%. The most abundant monoterpene was E-myrcene, followed by trans-caryophyllene, D-pinene, trans-ocimene, and D-terpinolene. “Drug-type” Cannabis plant generally contained less caryophyllene oxide than “fiber-type,” but even in “drug-type,” the THC content of the essential oil was not more than 0.08%.
The 50 known hydrocarbons detected in Cannabis sativa consist of n-alkanes ranging from C9 to C39, 2-methyl-, 3-methyl-, and some dimethyl alkanes. Cannabis sativa L. is one of the rare psychotropic plants in which the central nervous system activity is not linked to particular alkaloids. However, two spermidine-type alkaloids (cannabisativine and anhydrocannabisativine) have been identified among more than 70 nitrogen-containing constituents, and five lignanamide derivatives have been isolated, including cannabisin A, B, C, and D. Besides, twelve simple amines, including piperidine, hordenine, methylamine, ethylamine, and pyrrolidine, are present in Cannabies; three proteins: edestin, zeatin, and zeatinnucleoside; six enzymes: edestinase, glucosidase, polyphenoloxydase, peptidase, peroxidase, and adenosine-5-phosphatase; and 18 amino acids that are of a common structure for plants.
Thirteen monosacharides (fructose, galactose, arabinose, glucose, mannose, rhamnose, etc.), two disaccharides (sucrose, maltose), and five polysaccharides (raffinose, cellulose, hemicellulose, pectin, xylan) have been identified so far. In addition, 12 sugar alcohols and cyclitols (mannitol, sorbitol, glycerol, inositol, quebrachitol, etc.) and two amino sugars (galactosamine, glucosamine) were found; as well as twenty-three commonly occurring flavonoids have been identified in Cannabis plant, existing mainly as C-/O- and O-glycosides of the flavon- and flavonol-type aglycones apigenin, luteolin, quercetin, and kaempferol. Thirty-four noncannabinoid phenols are known to be present in Cannabis plant: nine with spiro-indan-type structure (e.g., cannabispiran, isocannabispiran), nine dihydrostilbenes (e.g., cannabistilbene I, -II), three dihydrophenanthrenes (e.g., cannithrene-1, -2), and six phenols, phenol methylethers, and phenolic glycosides. Seven alcohols (e.g., methanol, ethanol, 1-octene-3-ol), 12 aldehydes (e.g., acetaldehyde, isobutyraldehyde, pentanal), 13 ketones (e.g., acetone, heptanone-2, 2-methyl-2-heptene-6-one), and 21 acids (e.g., arabinic acid, azealic acid, gluconic acid) have also been identified. Cannabis also contains phytosterols: campesterol, ergosterol, E-sitosterol, and stigmasterol, as well as vitamin K, which is the only vitamin found in Cannabis, whereas carotene and xanthophylls are reported pigments; and 18 elements were detected as well (e.g., Na, K, Ca, Mg, Fe, Cu, Mn, Zn, Hg).
Prior to the late 1990's, nearly all chemical studies of Kratom activity focused on mitragynine with the assumption that mitragynine was the main active alkaloid in Mitragyna speciosa. With 7-hydroxymitragynine now clearly identified as the principal psychoactive alkaloid in Kratom, many elements of these studies must be revised. The variety of alkaloids discovered in diverse Kratom samples to date, still calls for further studies and experimentation, investigating their specific activity, effects and potential applications. Through its makeup and tradition of use, it is clear Mitragyna speciosa is much more than a simple opioid-like narcotic and mild stimulant. Many of the secondary chemicals found in Mitragyna speciosa are present in small yet appreciable quantities, and their synergetic role and activity in the general pharmacology of Mitragyna speciosa is not yet fully understood. Nonetheless, Kratom provides an opportunity for researchers and pharmaceutical industry to develop new medicines that are potentially safer and more effective. And even more so, when certain Kratom alkaloids are combined with cannabis the pharmacological effect is amplified.
One embodiment of this invention proposes several potentially more safe and effective compounds of Mitragyna speciosa and Cannabis sativa alkaloids that are extracted, purified and combined to provide a pharmaceutical-grade compound for treatment of pain and other symptoms associated with diseases, disorders, medical conditions, and having other applications that are contemplated by this invention. Another embodiment of this invention provides an effective drug delivery system that allows timed release of the active ingredients necessary to achieve high efficacy with minimum side effects. Another embodiment of this invention describes methodologies for effective treatment of patients having the medical and other conditions contemplated by this invention.
As already mentioned, Mitragyna speciosa contains certain alkaloids, such as the 7-hydroxymitragynine and mitragynine that reportedly exhibit more potent analgesic actions than that of morphine and having reduced side effects, most importantly—significantly reduced respiratory depression and lesser addiction liability due to the presence of kappa-opioid receptor antagonists (Kruegel, et al., 2016), relatively analogous in mechanism of action to the drug buprenorphine. The multiple receptor targets are beneficial in the treatment of pain, and especially complex pain syndromes, such as the neuropathic pain. But unlike the buprenorphine, in some embodiments, when certain Kratom alkaloids are combined with cannabinoids, such as THC, the proposed compound provides vasodilating, antihypertensive, muscle relaxing, immune-stimulating, anti-inflammatory, antipyretic, anti-arrhythmic, antitussive, and mild adrenergic effects, where the mild stimulating effect of mitragynine (in low doses) and THC helps to reduce drowsiness associated with higher doses of opioids or opioid-like substances.
Despite the addiction and other concerns, morphine and its derivatives remain to be the primary medicines to treat severe pain. Cannabis-based medicines are also now being offered for treatment of muscle spasticity in patients with MS. For example, Sativex—a CB extract oral spray containing THC and CBD—is known to relieve many MS symptoms. Sativex and other CB-based medicines can be used to treat neuropathic pain, nausea associated with cancer chemotherapy, as well as stimulate appetite in HIV patients. Nevertheless, morphine remains to be the indispensable analgesic for improving patients' quality of life (QOL) in the cases of cancer and other illnesses causing severe pain. However, morphine has problems of, for example, having low bioavailability and causing various side effects, such as formation of analgesic resistance and physical or psychological dependence due to continued use, nausea and vomiting, constipation, sleepiness, and most importantly respiratory depression.
With that said, the advent of a potent and more safe analgesic, serving as a substitute for morphine, has long been needed. In search of such analgesics, investigations of synthetic analogs were performed with chemical modification of a morphine molecule, starting the 1920s and until the present day. Many compounds were synthesized since then and evaluated. However, there are not many examples of an opioid analgesic substance that is as effective as morphine or its synthetic analogs but safer than them. Current research has focused on an analgesic action of morphine and efforts are currently made to elucidate a molecular mechanism of analgesia on the basis of, for example, classification of opioid receptors (δ-, μ- and κ-receptors) and determination of amino acid sequences thereof. However, there are complicated interactions among those three kinds of receptors, and a logical methodology for separating an analgesic property from side effects, such as a narcotic property, has not been established to date.
Several other opioid pharmaceutical products exist which provide analgesic relief but at the same time may have fewer side effects and lesser addiction liability. For example, buprenorphine, sold under the brand name Subutex, among others, is an opioid used to treat opioid addiction, acute pain, and chronic pain. It comes in injectable, transdermal, sublingual, and other dosage forms. Maximum pain relief is generally achieved within an hour with effects lasting up to 24 hours. Buprenorphine affects different types of opioid receptors in different ways. In simplified terms, buprenorphine can essentially be thought of as a non-selective, mixed agonist—antagonist opioid receptor modulator, acting as a weak partial agonist of the MOR, an antagonist of the KOR, an antagonist of the DOR, and a relatively low-affinity, very weak partial agonist of the ORL-1. Full analgesic efficacy of buprenorphine requires both exon 11 and exon 1-associated μ-opioid receptor splice variants. Side effects may include respiratory depression, sleepiness, adrenal insufficiency, QT prolongation, low blood pressure, allergic reactions, and opioid addiction. Among those with a history of seizures, there is a risk of further seizures. Opioid withdrawal following stopping is generally mild.
Tramadol is another opioid pharmaceutical product that provides analgesic relief but has fewer side effects and reduced addiction liability. Tramadol is sold under the brand name Ultram, among others, and it is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually occurs within an hour. It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain. It works by binding to the μ-opioid receptor and as a serotonin-norepinephrine reuptake inhibitor (SNRT). Tramadol is in the benzenoid class, and in the body, it is converted to desmetramadol, which is a more potent opioid. Common side effects include: constipation, itchiness and nausea. Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Long-term use of high doses of tramadol will cause physical dependence and withdrawal syndrome. Tramadol withdrawal typically lasts longer than that of codeine and other weak opioids (seven days or more of acute withdrawal symptoms). However, according to a 2014 report by the World Health Organizations Expert Committee on Drug Dependence, evidence of tramadol physical dependence was considered minimal. Consequently, tramadol is generally considered to be a drug with low potential for dependence.
There are a number of opioid receptor-modulating investigational analgesics that are currently under development for clinical use. For example: Axelopran/oxycodone—combination of a centrally active μ-opioid receptor agonist and a peripherally selective μ-, κ-, and δ-opioid receptor antagonist; Cebranopadol (GRT-6005)—non-selective μ-opioid receptor, nociceptin receptor, and δ-opioid receptor full agonist and κ-opioid receptor partial agonist; Desmetramadol (O-desmethyltramadol; Omnitram)—μ-opioid receptor agonist, norepinephrine reuptake inhibitor (NRI), and 5-HT2C receptor antagonist; Difelikefalin (CR845, FE-202845)—peripherally selective κ-opioid receptor agonist. Lexanopadol (GRT-6006, GRT13106G)—non-selective opioid receptor agonist; Nalbuphine sebacate (dinaphine, sebacoyl dinalbuphine ester; LT-1001)—long-lasting prodrug of nalbuphine, μ- and κ-opioid receptor partial agonist; NKTR-181-selective μ-opioid receptor full agonist that slowly enters the brain; Oliceridine (TRV130)—μ-opioid receptor biased agonist; Oxycodone/naltrexone—combination of a μ-opioid receptor agonist and a μ- and κ-opioid receptor antagonist, and others.
A study was undertaken to determine the analgesic and anti-inflammatory activity of various CBs and CB pre-cursors. Oral administration of CBD was found to be the most effective at inhibition of phenyl-p-benzoquinone-induced writhing in mice. It was noted that with the exception of CBN and delta 1-THC, the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. Delta 1-THC only became maximally effective in doses of 10 mg/kg (this higher dose corresponded to that which induced catalepsy and is indicative of a central action). CNB demonstrated little activity and even at doses higher than 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. And as mentioned earlier, CBD was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. Formukong et al. (1988) conclude that delta 1-THC and CBN were the least effective in this test, suggesting a structural relationship between analgesic activity and anti-inflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.
Thus, considering the many therapeutic effects, and specifically the analgesic effect of compounds containing CBs, particularly CBD and (−)-Δ9-trans-THC, there is a continuing need for improving existing CB-containing products as well as a need for new products and delivery systems containing CBs, especially in the pharmaceutical field.
Recent methods have also sought to find new ways to deliver CBs to a patient including those which bypass the stomach and the associated first pass effect of the liver which can remove up to 90% of the active ingested dose and avoid the patient having to inhale unhealthy tars and associated carcinogens into their lungs. Such dosage forms include administering the CBs to the sublingual or buccal mucosae, inhalation of a CB vapor by vaporization or nebulization, enemas or solid dosage forms such as gels, capsules, tablets, pastilles and lozenges.
To attain the required purity of isolated CBs and Kratom alkaloids, up to at least 97% by total weight, consistent ratio of CBs and Kratom alkaloids in the formulation, attain pharmaceutical-grade stability of active CBs and Kratom alkaloids, effective and consistent delivery system for treating multiple conditions, as well as therapeutically-effective treatment methods—requires a know-how that is proposed in this document.
As already mentioned, one objective of this invention is to provide a compound that has a potent analgesic action, which may serve as a substitute for morphine—a pharmaceutical composition and a treatment method. The novel compositions and treatment methods, with several variations, some of which are exemplified herein, exhibit a potent analgesic, anti-inflammatory, and muscle relaxing actions, and other actions contemplated by this invention. The proposed invention has relied on new scientific findings, experiments and anecdotal evidence obtained through this research. Inventors believe that this invention is unique and different from the existing art related to Mitragyna speciosa-based and Cannabis sativa-based compounds, processes, and methods. Some of the existing art is briefly outlined below.
The U.S. Pat. No. 7,968,594 referenced herein, discloses the invention that relates to treatment of cancer related pain and constipation. The subject in need is administered a combination of CBD and delta-9-THC in a predefined ratio by weight of approximately 1:1 of CBD to THC (U.S. Pat. No. 7,968,594, 2005).
The U.S. patent application Ser. No. 15/032,070 referenced herein, discloses a formula of compound containing 7-hydroxymitragynine that has an analgesic effect and high metabolic stability. The invention further provides the following: an analgesic obtained from the compound, a salt thereof, or solvates of the compound and salt; a pharmaceutical composition containing the compound, a salt thereof, or solvates of the compound and salt; an analgesic treatment method using the compound, a salt thereof, or solvates of the compound and salt; and a use of the compound, a salt thereof, or solvates of the compound and salt, in the production of an analgesic composition (U.S. Pat. No. 15,032,070, 2014).
The U.S. Pat. Application No. 20110245287 referenced herein, discloses hybrid opioid compounds, mixed opioid salts, compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof that among other substances may contain Kratom alkaloids. More particularly, in one aspect the hybrid opioid compound includes at least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical compositions, as well as methods of treating pain in humans using the hybrid compounds and mixed opioid salts (U.S. Pat. No. 20,110,245,287, 2011).
The U.S. Pat. Ser. No. 13/024,298 referenced herein, discloses a compound that may contain Kratom alkaloids, being a pharmaceutically acceptable salt or ester thereof, and a method of treating a subject afflicted with pain, a depressive disorder, a mood disorder or an anxiety disorder by administering the compound to the subject (U.S. Pat. No. 13,024,298, 2011).
The U.S. Pat. Application No. 20060135599 referenced herein, discloses the invention that relates to the use of one or more CBs in the treatment of neuropathic or chronic pain. A method of treating brachial plexus avulsion in a human patient comprising administering to a patient in need thereof effective amount one or more CBs (U.S. Pat. No. 20,060,135,599, 2003).